Live Imaging of Neuroinflammation Reveals Sex and Estrogen Effects on Astrocyte Response to Ischemic Injury

We sought to develop a model system for live analysis of brain inflammatory response in ischemic injury. Using a reporter mouse-expressing luciferase gene under transcriptional control of the murine glial fibrillary acidic protein (GFAP) promoter (GFAP-luc mice) and biophotonic/bioluminescent imagin...

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Veröffentlicht in:Stroke (1970) 2008-03, Vol.39 (3), p.935-942
Hauptverfasser: CORDEAU, Pierre, LALANCETTE-HEBERT, Mélanie, YUAN CHENG WENG, KRIZ, Jasna
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container_issue 3
container_start_page 935
container_title Stroke (1970)
container_volume 39
creator CORDEAU, Pierre
LALANCETTE-HEBERT, Mélanie
YUAN CHENG WENG
KRIZ, Jasna
description We sought to develop a model system for live analysis of brain inflammatory response in ischemic injury. Using a reporter mouse-expressing luciferase gene under transcriptional control of the murine glial fibrillary acidic protein (GFAP) promoter (GFAP-luc mice) and biophotonic/bioluminescent imaging as tools, we developed a model system for in vivo analysis of astrocyte activation/response in cerebral ischemia. Analysis of photon emissions from the brains of living animals revealed marked sex differences in astrocyte response to ischemic injury. The increase in GFAP signals was significantly higher in female mice in the metestrus/diestrus period compared with male transgenic mice (1.71 x 10(7)+/-0.19 x 10(7) vs 0.92 x 10(7)+/-0.15 x 10(7), P
doi_str_mv 10.1161/STROKEAHA.107.501460
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Using a reporter mouse-expressing luciferase gene under transcriptional control of the murine glial fibrillary acidic protein (GFAP) promoter (GFAP-luc mice) and biophotonic/bioluminescent imaging as tools, we developed a model system for in vivo analysis of astrocyte activation/response in cerebral ischemia. Analysis of photon emissions from the brains of living animals revealed marked sex differences in astrocyte response to ischemic injury. The increase in GFAP signals was significantly higher in female mice in the metestrus/diestrus period compared with male transgenic mice (1.71 x 10(7)+/-0.19 x 10(7) vs 0.92 x 10(7)+/-0.15 x 10(7), P&lt;0.001). Similar results were obtained by quantitative immunohistochemistry (males vs females: 13.4+/-0.5 vs 16.96+/-0.64, P&lt;0.0001). However, astrocyte activation/GFAP signals showed cyclic, estrus-dependent variations in response to ischemic injury. Physiologically higher levels of estrogen and application of pharmacologic doses of estrogen during replacement therapy attenuated GFAP upregulation after stroke. Interestingly, contrary to a positive correlation between the intensities of GFAP signals and infarct size in male mice, no such correlation was observed in any of the experimental groups of female GFAP-luc mice. Our results suggest that GFAP upregulation in ischemic injury may have different functional significance in female and male experimental animals and may not directly reflect the extent of ischemia-induced neuronal damage in female GFAP-luc mice. 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Using a reporter mouse-expressing luciferase gene under transcriptional control of the murine glial fibrillary acidic protein (GFAP) promoter (GFAP-luc mice) and biophotonic/bioluminescent imaging as tools, we developed a model system for in vivo analysis of astrocyte activation/response in cerebral ischemia. Analysis of photon emissions from the brains of living animals revealed marked sex differences in astrocyte response to ischemic injury. The increase in GFAP signals was significantly higher in female mice in the metestrus/diestrus period compared with male transgenic mice (1.71 x 10(7)+/-0.19 x 10(7) vs 0.92 x 10(7)+/-0.15 x 10(7), P&lt;0.001). Similar results were obtained by quantitative immunohistochemistry (males vs females: 13.4+/-0.5 vs 16.96+/-0.64, P&lt;0.0001). However, astrocyte activation/GFAP signals showed cyclic, estrus-dependent variations in response to ischemic injury. Physiologically higher levels of estrogen and application of pharmacologic doses of estrogen during replacement therapy attenuated GFAP upregulation after stroke. Interestingly, contrary to a positive correlation between the intensities of GFAP signals and infarct size in male mice, no such correlation was observed in any of the experimental groups of female GFAP-luc mice. Our results suggest that GFAP upregulation in ischemic injury may have different functional significance in female and male experimental animals and may not directly reflect the extent of ischemia-induced neuronal damage in female GFAP-luc mice. Using a novel live imaging approach, we demonstrated that the early-phase brain inflammatory response to ischemia may be associated with sex-specific biomarkers of brain damage.</description><subject>Animals</subject><subject>Astrocytes - pathology</subject><subject>Biological and medical sciences</subject><subject>Brain Ischemia - complications</subject><subject>Brain Ischemia - metabolism</subject><subject>Brain Ischemia - pathology</subject><subject>Cerebral Infarction - etiology</subject><subject>Cerebral Infarction - pathology</subject><subject>Diestrus</subject><subject>Encephalitis - diagnosis</subject><subject>Encephalitis - etiology</subject><subject>Encephalitis - metabolism</subject><subject>Estrogens - metabolism</subject><subject>Estrogens - pharmacology</subject><subject>Female</subject><subject>Glial Fibrillary Acidic Protein - genetics</subject><subject>Glial Fibrillary Acidic Protein - metabolism</subject><subject>Immunohistochemistry</subject><subject>Luminescence</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metestrus</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neurology</subject><subject>Neuropharmacology</subject><subject>Neuroprotective agent</subject><subject>Pharmacology. Drug treatments</subject><subject>Sex Factors</subject><subject>Up-Regulation - drug effects</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>0039-2499</issn><issn>1524-4628</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtPGzEUha2KqgTaf1BV3sBugl_jxzJCoUSNQAK6Hjme63TojJ3aM6j59xglosuu7tXRd8-R7kHoKyVzSiW9enx6uP-xXNwu5pSoeU2okOQDmtGaiUpIpk_QjBBuKiaMOUVnOT8TQhjX9Sd0SjWrtWZqhn6vuxfAq8Fuu7DF0eM7mFLsgu_tMNixiwE_wAvYPuNH-IttaPEyjyluIeCl9-DGjAuzeNPcfoRC510MGfAY8Sq7XzB0Dq_C85T2n9FHX4zgy3Geo583y6fr22p9_311vVhXThg9VsBbzi1jrTdctkwoULpsJQwkoxsjqBFGcM2YlC1Ix4XY-FbLmipSS8n5Obo8-O5S_DNBHpuhyw763gaIU24U4aK8Rv0XLEGK1UwXUBxAl2LOCXyzS91g076hpHlro3lvoyiqObRRzr4d_afNAO2_o-P7C3BxBGx2tvfJBtfld46RYq2F4a_k15LS</recordid><startdate>20080301</startdate><enddate>20080301</enddate><creator>CORDEAU, Pierre</creator><creator>LALANCETTE-HEBERT, Mélanie</creator><creator>YUAN CHENG WENG</creator><creator>KRIZ, Jasna</creator><general>Lippincott Williams &amp; Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20080301</creationdate><title>Live Imaging of Neuroinflammation Reveals Sex and Estrogen Effects on Astrocyte Response to Ischemic Injury</title><author>CORDEAU, Pierre ; LALANCETTE-HEBERT, Mélanie ; YUAN CHENG WENG ; KRIZ, Jasna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-e3d33a22df936d247e78936ffee621b9419494382266de6c344bfd86517056633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Astrocytes - pathology</topic><topic>Biological and medical sciences</topic><topic>Brain Ischemia - complications</topic><topic>Brain Ischemia - metabolism</topic><topic>Brain Ischemia - pathology</topic><topic>Cerebral Infarction - etiology</topic><topic>Cerebral Infarction - pathology</topic><topic>Diestrus</topic><topic>Encephalitis - diagnosis</topic><topic>Encephalitis - etiology</topic><topic>Encephalitis - metabolism</topic><topic>Estrogens - metabolism</topic><topic>Estrogens - pharmacology</topic><topic>Female</topic><topic>Glial Fibrillary Acidic Protein - genetics</topic><topic>Glial Fibrillary Acidic Protein - metabolism</topic><topic>Immunohistochemistry</topic><topic>Luminescence</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metestrus</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neurology</topic><topic>Neuropharmacology</topic><topic>Neuroprotective agent</topic><topic>Pharmacology. Drug treatments</topic><topic>Sex Factors</topic><topic>Up-Regulation - drug effects</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CORDEAU, Pierre</creatorcontrib><creatorcontrib>LALANCETTE-HEBERT, Mélanie</creatorcontrib><creatorcontrib>YUAN CHENG WENG</creatorcontrib><creatorcontrib>KRIZ, Jasna</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Stroke (1970)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CORDEAU, Pierre</au><au>LALANCETTE-HEBERT, Mélanie</au><au>YUAN CHENG WENG</au><au>KRIZ, Jasna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Live Imaging of Neuroinflammation Reveals Sex and Estrogen Effects on Astrocyte Response to Ischemic Injury</atitle><jtitle>Stroke (1970)</jtitle><addtitle>Stroke</addtitle><date>2008-03-01</date><risdate>2008</risdate><volume>39</volume><issue>3</issue><spage>935</spage><epage>942</epage><pages>935-942</pages><issn>0039-2499</issn><eissn>1524-4628</eissn><coden>SJCCA7</coden><abstract>We sought to develop a model system for live analysis of brain inflammatory response in ischemic injury. Using a reporter mouse-expressing luciferase gene under transcriptional control of the murine glial fibrillary acidic protein (GFAP) promoter (GFAP-luc mice) and biophotonic/bioluminescent imaging as tools, we developed a model system for in vivo analysis of astrocyte activation/response in cerebral ischemia. Analysis of photon emissions from the brains of living animals revealed marked sex differences in astrocyte response to ischemic injury. The increase in GFAP signals was significantly higher in female mice in the metestrus/diestrus period compared with male transgenic mice (1.71 x 10(7)+/-0.19 x 10(7) vs 0.92 x 10(7)+/-0.15 x 10(7), P&lt;0.001). Similar results were obtained by quantitative immunohistochemistry (males vs females: 13.4+/-0.5 vs 16.96+/-0.64, P&lt;0.0001). However, astrocyte activation/GFAP signals showed cyclic, estrus-dependent variations in response to ischemic injury. Physiologically higher levels of estrogen and application of pharmacologic doses of estrogen during replacement therapy attenuated GFAP upregulation after stroke. Interestingly, contrary to a positive correlation between the intensities of GFAP signals and infarct size in male mice, no such correlation was observed in any of the experimental groups of female GFAP-luc mice. Our results suggest that GFAP upregulation in ischemic injury may have different functional significance in female and male experimental animals and may not directly reflect the extent of ischemia-induced neuronal damage in female GFAP-luc mice. Using a novel live imaging approach, we demonstrated that the early-phase brain inflammatory response to ischemia may be associated with sex-specific biomarkers of brain damage.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>18258827</pmid><doi>10.1161/STROKEAHA.107.501460</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Alma/SFX Local Collection; EZB Electronic Journals Library; American Heart Association; Journals@Ovid Complete
subjects Animals
Astrocytes - pathology
Biological and medical sciences
Brain Ischemia - complications
Brain Ischemia - metabolism
Brain Ischemia - pathology
Cerebral Infarction - etiology
Cerebral Infarction - pathology
Diestrus
Encephalitis - diagnosis
Encephalitis - etiology
Encephalitis - metabolism
Estrogens - metabolism
Estrogens - pharmacology
Female
Glial Fibrillary Acidic Protein - genetics
Glial Fibrillary Acidic Protein - metabolism
Immunohistochemistry
Luminescence
Male
Medical sciences
Metestrus
Mice
Mice, Transgenic
Neurology
Neuropharmacology
Neuroprotective agent
Pharmacology. Drug treatments
Sex Factors
Up-Regulation - drug effects
Vascular diseases and vascular malformations of the nervous system
title Live Imaging of Neuroinflammation Reveals Sex and Estrogen Effects on Astrocyte Response to Ischemic Injury
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